Basolateral Efflux Transporters: A Potentially Important Pathway for the Prevention of Cholestatic Hepatotoxicity

Abstract

The hepatocyte adaptive response has been postulated to play a protective role in cholestatic disease states, including primary biliary cirrhosis where bile acid biliary efflux is reduced. Regulation of bile acid synthesis by farnesoid X receptor (FXR) has been well defined; however, bile acid transport has not. Utilizing sandwich-cultured human hepatocytes (SCHH) and B-CLEAR® technology, we demonstrated that basolateral efflux and not canalicular efflux (bile salt export pump [BSEP]) was the primary driver of bile acid intracellular accumulation. Following 72 hours of exposure to CDCA, decreases of total endogenous bile acid mass and CYP7A1 mRNA content were observed in SCHH consistent with FXR activation. No marked changes were observed in mRNA content of bile acid uptake transporters, however, induction of bile acid efflux transporters OSTα (3.1–6.8 × ), OSTβ (21–187 × ), and BSEP (2.2–7.5 × ) mRNA content was observed. While decreases of d8-TCA biliary clearance were inconsistent with the increases in BSEP mRNA content, decreases in the intracellular concentrations of the model bile acid, d8-TCA, were observed in SCHH following CDCA exposure. Overall, these data suggest that basolateral efflux of bile acids via OSTα/β is a potentially important compensatory mechanism to prevent cholestatic hepatotoxicity.